Cancer Metabolism

Lead Research Organisation: The Francis Crick Institute

Abstract

The metabolism of nutrients by various biochemical processes is essential for life. Perturbations in metabolic pathways have long been implicated in disease and provide potential avenues for therapeutic intervention. Our lab is investigating how metabolism is altered in disease and we are using this knowledge to propose rational ways for treating and preventing cancer.
Towards this goal, we are elucidating the mechanism by which nutrients found in our diet and generated by our bodies influence the function of proteins at the atomic level and how such mechanisms control metabolic processes in health and disease. We have a particular interest in liver cancer, which has been epidemiologically linked to liver damage caused by diet. The ultimate aim is to identify novel ways to prevent the development of liver cancer in individuals with pre-malignant liver disease.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

The overall aim of my lab is to elucidate the fundamental principles that govern the spatiotemporal regulation of metabolism in mammalian organisms. The ultimate goal is to understand how these mechanisms are perturbed in disease and use this knowledge to design novel pharmacological approaches for cancer therapy and prevention. Towards these goals, research in my lab focuses on three complementary approaches:
(1) We use in vivo metabolic tracer studies and metabolic imaging in mouse models of liver regeneration and disease to investigate how metabolic communication between organs is altered during tumorigenesis to support cancer growth. These studies indicate that tumours engage in an intricate metabolic cross-talk between various organs to re-programme metabolism throughout the mammalian body which leads to the use of nutrients not normally implicated in normal organ function.
(2) We develop physiologically relevant tissue culture models of cancer that we use for metabolic tracer studies to understand the role of subcellular compartmentalisation in metabolic regulation. This work, complemented by biochemical reconstitution of metabolic pathways in vitro has uncovered new insights into the mechanisms by which metabolic pathways separated in different cellular niches are coordinated and point to a critical role for these mechanisms in supporting cancer cell survival in response to stress.
(3) We use computational modelling to predict the allosteric pathways through which metabolites influence protein function and use this information to engineer proteins with altered allosteric properties that can be controlled in a reversible manner through optogenetic methods. As allostery is crucial for the rapid adaptation of metabolic pathways to environmental cues, our studies provide a framework for predicting and designing novel allosteric modulators to interfere with the pathways discovered through directions 1 and 2 in cancer.
Overall, since its foundation, our research programme has provided novel insights into less understood aspects of metabolic regulation thereby informing the rational targeting of metabolic pathways that contribute to tumorigenesis. We have also developed a series of mouse models and computational methods that allowed us to investigate regulation mechanisms in glucose metabolism but are broadly applicable to other metabolic pathways.

Publications

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